title: Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas.
abstract: PPP2R1A mutations have recently been described in 3/42 (7%) of clear cell carcinomas of the ovary. PPP2R1A encodes the α-isoform of the scaffolding subunit of the serine/threonine protein phosphatase 2A (PP2A) holoenzyme. This putative tumour suppressor complex is involved in growth and survival pathways. Through targeted sequencing of PPP2R1A, we identified somatic missense mutations in 40.8% (20/49) of high-grade serous endometrial tumours, and 5.0% (3/60) of endometrial endometrioid carcinomas. Mutations were also identified in ovarian tumours at lower frequencies: 12.2% (5/41) of endometrioid and 4.1% (2/49) of clear cell carcinomas. No mutations were found in 50 high-grade and 12 low-grade serous carcinomas. Amino acid residues affected by these mutations are highly conserved across species and are involved in direct interactions with regulatory B-subunits of the PP2A holoenzyme. PPP2R1A mutations in endometrial high-grade serous carcinomas are a frequent and potentially targetable feature of this disease. The finding of frequent PPP2R1A mutations in high-grade serous carcinoma of the endometrium but not in high-grade serous carcinoma of the ovary provides clear genetic evidence that these are distinct diseases.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, 3427-600 West 10th Avenue, Vancouver, BC, Canada.
authors.forename: Melissa K
authors.initials: MK
authors.lastname: McConechy
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Winnie
authors.initials: W
authors.lastname: Yang
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Christine
authors.initials: C
authors.lastname: Chow
authors.forename: Alireza
authors.initials: A
authors.lastname: Heravi-Moussavi
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Morin
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Mark S
authors.initials: MS
authors.lastname: Carey
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.forename: Janice S
authors.initials: JS
authors.lastname: Kwon
authors.forename: Leah M
authors.initials: LM
authors.lastname: Prentice
authors.forename: Niki
authors.initials: N
authors.lastname: Boyd
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics; D018269:Carcinoma, Endometrioid / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D054648:Protein Phosphatase 2 / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; C517191:PPP2R1A protein, human; D054648:Protein Phosphatase 2